Friday, 31 May 2013

Matthew Herper. Biogen Idec's MS Drug Launch Is Going Amazingly Well. These Two Graphs Prove It. PHARMA & HEALTHCARE . 5/29/2013 @ 11:16AM Sales of the dimethyl fumarate (Tecfidera) are destroying what were already very high expectations. Mark Schoenebaum at International Strategy & Investment Group noted on Tuesday that according to data from IMS Health, prescriptions for Tecfidera went up 21% last week. Even if MSers start dropping off the drug at a 10% rate and weekly additions slow, US sales could hit $800 million this year, about double what analysts had expected before the launch. The following graph is Schoenebaum’s, and it compares dimethyl fumarate's (Tecfidera) launch to those of fingolimod and teriflunomide, the other oral agents.

"We wonder what would have happened if oral cladribine had been given a license? The cladribine CIS or Oracle Study was better than expected and demonstrates what the field is missing; a well tolerated high-efficacy oral that is an induction therapy. We wonder what effect a generic cheap cladribine would have on the market?"

Biomarkers capable of predicting the clinical course and the rate of disease progression in multiple sclerosis are currently unavailable. Our objective was to examine if the levels of proteins associated with axonal and neuronal degeneration (Tau and β-amyloid) and T-cell-mediated autoimmunity (osteopontin) are altered in the cerebrospinal fluid (CSF) of MS patients, and to assess their potential in reflecting the clinical severity and predicting the progression and clinical evolution of early MS. The CSF samples collected from patients presenting with different clinical forms of MS were evaluated by enzyme-linked immunosorbent assays. The patients were regularly followed-up and their clinical status was re-evaluated 5 years after sampling. The results demonstrated that while CSF levels of Tau and β-amyloid did not differ between MS and Control groups, the levels of osteopontin were significantly elevated in MS patients. This increase was associated with the presence of a relapse and correlated with clinical severity, which findings were independent of age and blood-CSF barrier function. However, none of the examined protein levels differed significantly between groups with different clinical evolutions and no positive correlations with clinical progression could be detected. We conclude that Tau and β-amyloid are inappropriate as biomarkers in MS. This is the first report on CSF osteopontin as an independent marker of clinical severity in definite MS.

Tau and B amyloid are proteins have been associated with Alzheimers disease, but also get expressed in the brains of MSers either as part of or inresponse to the disease process. This study could not link the presence of these proteins to disease course, but this is not the case with osteopontin. Osteopontin is a bone protein that was later found to affect T cell (white blood cell function).

This study reports that it is a marker of inflammation. This work confirms previous studies that reported that "osteopontin concentration in the cerebrospinal fluid (CSF) is a dynamic indicator of disease activity in relapsing remitting MS, presumably reflecting ongoing inflammation. Increased CSF osteopontin concentrations in primary progressive MS may indicate ongoing inflammation even in these patients"

"I am in Istanbul at the 2013 CME Annual meeting in MS: How to translate new insights in MS into clinical practice. I have a very difficult talk to give on day 2 of the meeting; I am not sure what to speak about. I leaning towards MS Prevention."

"Istanbul is one city that makes you realise how insignificant you are in the scale of history; its size (~15M people), its position (where Europe meets Asia), its importance (it was the centre of the four different empires (Roman, Byzantium, Latin and Ottoman) and its beauty. I have a view from my hotel room over the Bosphorus River, that is simply breathtaking."

"Back to the serious topic of MS and its affect on individuals and Society; I will keep you posted on the meeting and will upload my talks after I give them tomorrow."

VBM = voxel based morphometry morphs the brain onto a standard template and looks for subtle anatomical variations, for example shrinkage of the brain in a specific region.

TBSS= tract-based spatial statistics is a measure of how intact a particular nerve pathway is as well as its connections, for example the corticospinal tract from the cerebral cortex in the brain to the spinal cord, this is the tract that carries motor fibres. Damage to the corticospinal tract results in weakness, spasticity and so called clonic spasms.

CONCLUSIONS: Selective GM atrophy and widespread WM tracts damage are associated with functional impairment of upper-limb motion and cognition. The combined analysis of volumetric and DTI data may help to better understand structural alterations underlying physical and cognitive dysfunction in MS.

"This study is showing what we already know; MS is associated with widespread damage on MRI that correlates with clinical outcomes, for example upper-limb function (speed and accuracy of movement) and cognition. Cognition refers to the complex mental processes that include attention, memory, producing and understanding language, learning, reasoning, problem solving, and decision making."

"It is becoming increasingly clear that MRI is a window into the brain; what we are seeing on MRI is the pathology. This is not what some people in the field would like you to believe. What you see clinically is the tip of the iceberg and often reflects how well you adapt to damage. Some MSers have incredible functional reserve and cope with extraordinary amount of damage when their MRIs show major damage. The problem with this is that ultimately that MSer's coping mechanisms eventually fail and they develop overt disabilities and often appear to go downhill very rapidly. They go down rapidly because they accumulated so much damage in the past and it manifests itself as soon as a threshold is seen."

BACKGROUND: Multiple Sclerosis (MS) is a disabling chronic disease of the nervous system in which the myelin system of the central nervous system is deteriorated. The objective of this study is to understand the effect of Pilates exercises and aquatic training for a 12 week period on the dynamic balance of MS patients.

METHODS: The research method is semi-experimental. As a result, among the female patients visiting the MS clinic of Kashani hospital in Esfahan, 57 patients with disease intensity levels between 0 and 4.5 were taken as samples. The average length of the disease was 8 ± 2 years, 20;40 years old, and they were randomly divided into three groups of Pilates exercise group, aquatic training group, and the control group. The exercise schedule for the experiment groups consisted of 12 weeks, three sessions per week, and 1 hour for each session. The dynamic balance of the patients, before and after the exercises was measured by Six Spot Step Test.

RESULTS: The adjusted mean differences of Timed Up and Go Test (TUGT) scores of the experimental groups are significantly different (P<0.05). Therefore, it can be said that Pilates exercise interventions and aquatic training can significantly increase the dynamic balance of the examinees in the post-experiment stage.

CONCLUSIONS: Performing the Pilate exercises and aquatic training increases dynamic balance of the MS patients. Considering the role of dynamic balance on physical fitness and enabling the person in doing is daily chores and routines, and its direct effect on the quality of life, it leads the specialists in applying these exercises as a supplementary treatment along with the medicinal treatments for MS patients.

The six spot step test (click here) is a method to measure balance is used to assess your co-ordination and balance. The Timed Up and Go Test, or TUG Test (click here) is used to assess your mobility, and can be used to predict your likelihood of falling.

This study examined whether exercise could improve balance and they found that pilates and training in water can be benefical. Exercise for Health.

CONCLUSIONS: FACETS is effective in reducing fatigue severity and increasing fatigue self-efficacy. However, it is difficult to assess the additional cost in terms of cost-effectiveness (ie, cost per QALY) as improvements in fatigue are not reflected in the QALY outcomes, with no significant differences between FACETS and CLP. The strengths of this trial are its pragmatic nature and high external validity.

"Pragmatic trials; the new buzzword. What are pragmatic trials? A pragmatic trial aims to test a treatment or treatment policy in a 'real life' situation, when many MSers may not receive all of the treatment, and may use other treatments as well. This is as opposed to an explanatory trial, which is done under ideal conditions and is trying to determine whether a therapy has the ability to make a difference at all; i.e. testing its efficacy or effectiveness. In this pragmatic trial the investigators studied whether or or not a cognitive behavioural therapy and energy effectiveness techniques focusing on lifestyle helped MSers with fatigue. It appears it did. This is not surprising; in my experience when MSers with fatigue engage in a programme that requires them to be motivated and self-disciplined they note an improvement. In our area the local disability options teams help with this. Before embarking on this you need to makes sure that the person in question has addressed all the other elements associated with MS that affect fatigue, i.e. poor sleep hygiene, pain, spasms, nighttime stimulants, sedating medication, restless legs, bladder dysfunction, low mood or depression, anxiety, bladder and bowel dysfunction, etc. The good news is that fatigue may not be an intractable problem, if you have fatigue ask your neurological team if they can look into it."

"I am interested to know how many of you have had CBT or other therapies for fatigue."

Thursday, 30 May 2013

"My poster from the ISPOR 18th Annual International Meeting in New Orleans. The main finding is that BG12 or DMF reduces the proportion of relapses needing to be treated with intravenous steroids. Use of steroids is a surrogate for the severity of relapses; in other words BG12 not only reduces the number of relapse, but also the severity of relapses. This is good news as high-dose steroids are not without risks. As I have said before steroids can have severe side effects and should be avoided if possible."

As we have said many times inhibiting the actions of the immune response is on balance a good thing and can limit the factors driving MS. However in many progressive MSers there is active inflammation and dealing with this saves nerves. This can be see by a reduction in the production of neurofilament in brain fluid. This molecule (neurofilament) is in nerves and if they are not being damaged then neurofilament is not released, so damage is being stopped.

BACKGROUND: Axonal and neuronal damage are widely accepted as key events in the disease course of MS. However, it has been unclear to date at which stage in disease evolution neurodegeneration begins and whether neuronal damage can occur even in the absence of acute inflammatory attacks.

METHOD: 45 CISers and age- and sex-matched healthy controls were investigated using spectral domain optical coherence tomography (OCT). CISers' eyes were stratified into the following categories according to history of optic neuritis (ON): eyes with clinically-diagnosed ON (CIS-ON), eyes with suspected subclinical ON (CIS-SON) as indicated by a visual evoked potential latency of >115ms and eyes unaffected by ON (CIS-NON).

RESULTS: CIS-NON eyes showed significant reduction of ganglion cell- and inner plexiform layer and a topography similar to that of CIS-ON eyes. Seven eyes were characterized as CIS-SON and likewise showed significant retinal layer thinning. The most pronounced thinning was present in CIS-ON eyes.

CONCLUSION: Our findings indicate that retinal pathology does occur already in CIS. Intraretinal layer segmentation may be an easily applicable, non-invasive method for early detection of retinal pathology in patients unaffected by ON.

"Are you surprised with this result? This is another example of neuroaxonal pathology occurring early in the course of the disease. The question is whether or not this is being driven by sub-clinical inflammatory lesions or is part of a more widespread neurodegenerative process. I suspect it is the former. This hypothesis is currently being tested with early aggressive therapy that should prevent ongoing neuronal and axonal loss in early MS."

Background: Sexual concerns are known to be common in women MSers but definite data on the prevalence of particular sexual dysfunctions (SD) remain unclear. Previous studies brought inconsistent findings and rely on small groups of MSers or use of unvalidated assessment methods.

Objective: The aim of this research was to evaluate the prevalence of SD in women with MS using validated clinimetric scales.

Results: Only 2.2 % of MSers had ever discussed their sexual concerns with a physician. 70.1 % reported sexual activity. At least one SD could be found in 82.5 % of MSers, hypoactive sexual desire (57.7 %), arousal dysfunction (decreased genital sensation in 47.3 %, decreased lubrication in 48.4 %, decreased subjective arousal in 45.2 %) and orgasmic dysfunction (39.8 %) being the most probable. SD were less likely in women who assessed their relationship positively but more common in older MSers and those who had a positive history of depression. The prevalence of SD was higher comparing to the majority of studies by other authors.

Conclusions: SD are very common in female MSers and is frequently overlooked by medical professionals. Therefore, the assessment of sexual function should be implemented in all MSers after the diagnosis of MS. Further research is needed for better understanding of the sexuality of this particular population in order to establish targets for therapeutic intervention.

"Female sexual dysfunction is much commoner than I realised. It appears this problem is being ignored. What can be done about it? If you want to complete the index you can click on the links below and the appendix on how to score the index. I note the index is copyrighted therefore I am reluctant to set-up a survey on the blog to see if we can replicate the study's findings. Can I assume this post will generate a lot of debate?"

"I will need to discuss this with the team and see what can be done about this issue."

Tuesday, 28 May 2013

"I have volunteered to do a Twitter Chat to honor World MS Day. This is a live Q&A session via Twitter. Although I tweet daily and use Twitter all the time this will be my first live event. You are welcome to sign in to and participate. To participate you will need your own Twitter account. To follow the Chatter it is best to use TweetChat (www.tweetchat.com), a site dedicated to live Twitter conversations, or TweetDeck (www.tweetdeck.com); both these sites allow you track conversations using the # (hashtag). On Tuesday the hashtag that will be used is #HealthTalk"

In honor of World MS Day on May 29th, Everyday Health will co-host a live Twitter chat on Tuesday, May 28 at 6pm UK Summer Time or 1 pm EST, with experts from the National Multiple Sclerosis Society, plus other guests affiliated with the Society. Bruce Bebo, PhD, Associate VP of Discovery Research at the National MS Society, and Gavin Giovannoni, MBBCh, PhD, of the Blizard Institute, Barts and The London School of Medicine and Dentistry, will be with us to discuss the latest in MS research and treatments. We will also be joined by people living with multiple sclerosis, including Breea Renee, a young adult with MS, David Lyons, a body builder with MS, and Trevis Gleason, Everyday Health's Life With MS blogger. Bring your questions and share your own stories with us by following the hashtag #HealthTalk.

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen's encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer's disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.

The question is what drives the cortical lesions on the edge of the brain is it the same here in the grey matter, just like the white matter. The suggestion here is that the processes are very similar. We know that grey matter lesions contain less cells than white matte lesion. But the fact that they find T cell and microglial activation cues still indicates an immune driven effect. I would think that others like the antibod-driven cause andothers may say viral infection and immune attack.

Brain atrophy our next therapeutic target. #MSBlog #MSResearch"The following are the final brain atrophy survey results. They are very interesting.""It is clear that there is a knowledge gap, between what you want to know about your disease and what your neurology team are prepared to provide you, or they do not have the data to give you. The only way we are going to get brain atrophy up the agenda is for you to ask your neurologist about whether or not you have evidence of brain atrophy on your MRI. Unless the atrophy is gross atrophy, i.e. visible to the naked eye, most neurologists won't be able to say yes or no. Brain atrophy on MRI has to be measured using specialised software and normalised to a reference data set, or to an MRI you have had in the past."d"We at the Royal London Hospital don't get routine brain atrophy measurements. We have however, been collecting the correct data set to allow brain atrophy measurements. This is a so called 3D-acquisition, which will allow us to measure brain atrophy serially in MSers. Why will this be important? I think it will be one of the metrics that we include in the NEDA (no evidence of disease activity) composite. We will not only aim to prevent relapses, disease progression, new or enlarging T2 and Gd-enhancing lesions, but we will also aim to normalise the rate of brain atrophy. Brain atrophy is not a good thing and correlates with a poor outcome so preventing it should benefit MSers."

We need to get a grip on sleep disorders in MS; they are common. #MSBlog #MSResearch"Thank you all for completing the sleep disorder survey that has been running on the blog since early April. The following is a precis of the results."Number of MSers respondents = 146Mean age (standard deviation) = 45 yrs (SD 9.9)Youngest respondent = 23 yrsOldest respondent = 63 yrsSex: females = 64% & males = 36%Type of MS: CIS = 3%, RRMS = 67%, SPMS = 20% & PPMS = 10%Proportion of MSers with symptoms suggestive of sleep apnea – a potentially serious disorder which causes you to stop breathing repeatedly, often hundreds of times in the night during your sleep = 71%

Proportion of MSers with symptoms suggestive of insomnia – a persistent inability to fall asleep or stay asleep = 64%

Proportion of MSers with symptoms suggestive of narcolepsy or daytime hypersomnolence – a disorder characterized by uncontrollable sleep attacks during the day = 49%

"These results suggest that sleep disorders are very common in MS and need to be investigated. Poor sleep impacts massively on daytime functioning; it contributes to MS-related fatigue. If you score highly on these subscales of the screening questionnaire you should speak to your MS team. You may need to be investigated further."

Disclaimer: These results are based on a sleep disorder screening questionnaire; the prevalence of of these disorders will be lower in real life. Screening questionnaires, by design, overestimate the prevalence of the disorders before further investigations are done to specifically diagnose the condition in question.

Background: Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among MSers. This has raised interest in potential clinical benefits of vitamin D supplementation in the management of MS.

Objectives: The objectives were to examine the effect of vitamin D based interventions on the relative risk of relapse in MS.

Methods: Any randomised controlled trial assessing the effect on the relative risk of relapse of any formulation or dose of vitamin D, in participants with MS, was eligible. The inverse variance with random effects model in Review Manager 5.1 was used to calculate the odds ratio of relapses in high dose vitamin D treated patients vs. controls.

Results: Five studies were published as of September 2012, yielding a total of 129 high-dose vitamin D-treated patients and 125 controls. We found no significant association between high-dose vitamin D treatment and risk of MS relapse (OR 0.98, 95% CI 0.45-2.16).

Conclusion: In conclusion, although no significant association between high-dose vitamin D treatment and risk of MS relapses was found, the studies were limited by several methodological limitations. Further larger, more prolonged studies are merited.

"There is little evidence from published trials that high-dose vitamin D prevents or reduces relapses. The studies are too small to be confident about this result is why we need bigger and properly powered trials to assess the impact of vD on clinical outcomes. I don't use the possible disease-modifying effects of vD to promote high-dose supplementation in MS; I do so on the grounds of promoting bone health. MSers are more likely than controls have thin bones and fractures."

RESULTS: Treatment with fingolimod led to a marked reduction of CD3+ T cells with a relative decrease of naive and central memory T cells and an increase of effector memory T cells. Expression of the activation markers CD137 and CD69 upon VZV stimulation was unaltered by fingolimod. However, the absolute number of cells proliferating upon VZV stimulation was reduced in the blood of MSers treated with fingolimod. Also, VZV-specific and Epstein-Barr virus (EBV)-specific IFN-γ-producing cells were reduced after fingolimod therapy. Seven of the 35 MSers treated with fingolimod showed signs of VZV or EBV reactivation in saliva compared with 3 of the 111 controls. None of the 76 tested samples showed signs of viral reactivation in the peripheral blood mononuclear cells.

CONCLUSION: MSers treated with fingolimod show a slightly reduced antiviral T-cell response. This reduced response is accompanied by a subclinical reactivation of VZV or EBV in the saliva of 20% of MSers treated with fingolimod.

Varicella skin rash

Varicella penumonia

"What this study is testing is the ability of immune cells in the blood to respond to two herpes viruses, VZV (variella-zoster virus) and EBV (Epstein-Barr virus). VZV causes chicken pox and shingles and EBV infectious mononucleosis. There is little doubt that fingolimod reduces the ability of your T cells in the blood to respond to these viruses. This would partially explain the 3 deaths, that I am aware of in, in MSers on fingolimod due to herpses viruses; one case of herpes encephalitis and 2 cases of disseminated VZV."

"I am not sure if I wrote this paper that I would use the adjective 'slightly' to explain the reduction in antiviral T-cell responses due to fingolimod. It is as if the authors are wanting to play down their findings. Either fingolimod reduces or does not reduce anti-viral responses. This study shows it does. These results are not surprising as fingolimod is an immunosuppressive drug. What can be done about this reduction in anti-viral responses. All VZV negative MSers should have a VZV vaccine before starting fingolimod (this is part of our standard operating procedure) and MSers on fingolimod should be vigilant about infections. The latter is important as we have several antiviral drugs that work against some of the herpes viruses and if started quickly they should improve clinical outcomes."

"I must commend these investigators for doing this study; it is very important data that adds to our knowledge about fingolimod. I will also find it useful when counseling MSers about fingolimod."

"This highly technical paper explains that the migration of white blood cells into the brain and spinal cord of MSers is controlled by a protein that activates the production of enzymes that white cells use to tunnel their way into the brain and spinal cord tissues. By blocking this regulator, with a drug, you could potentially block migration of white cells into the brain and spinal cord. Is this important? Yes, we already know that blocking white cell entry into the brain and spinal cord is a very effective treatment for MS; this is how natalizumab or Tysabri works. This study describes another way of doing this. I assume Big Pharma are on the case already. How exactly you would do this is beyond the scope of this article, but is very complicated. Is the protein druggable, i.e. have an area that will bind to a small molecule that would inhibit it or will you need to target the pathway upstream by targeting the mRNA. The latter is done with small interfering RNA molecules that causes the message for the protein production to be broken down by another enzyme called dicer. I could go but will stop here. I hope all this makes sense."

Background: Inflammatory perivascular cuffs are comprised of leucocytes (white blood cells) that accumulate in the perivascular space (spaces around blood vessels) around post-capillary venules (blood vessels where white blood cells across into the brain) before their infiltration into the brain and spinal cord. Inflammatory perivascular cuffs are commonly found in the central nervous system of MSers and in the animal model experimental autoimmune encephalomyelitis (EAE). White blood cells that accumulate in the perivascular space secrete enzymes (matrix metalloproteinases) that aid their migration into the nervous tissue. The enzymes digest the proteins around the white cells allowing them to tunnel their way into the brain tissue.

These investigators' described previously that the upstream genetic inducer for the production of these enzymes (matrix metalloproteinase), the so called extracellular matrix metalloproteinase inducer, or CD147, is elevated in EAE, and that inhibiting this inducers reduces white cell entry into the central nervous system.

Objective: In this study the investigators' investigated whether the extracellular matrix metalloproteinase inducer varies with the temporal evolution of lesions in EAE and whether it was seen in MS lesions, and whether it was a feature of inflammatory perivascular cuffs in MS lesions.

Results: In EAE elevation of extracellular matrix metalloproteinase inducer was correlated with the appearance and persistence of clinical signs of disease. In both mouse and human samples, extracellular matrix metalloproteinase inducer was detected on endothelium (the lining of blood vessels) in healthy and disease states but was dramatically increased in and around inflammatory perivascular cuffs on leucocytes (white blood cells), associated with matrix metalloproteinase (enzyme that affects structural proteins) expression, and on resident cells including microglia. Leucocyte populations that express extracellular matrix metalloproteinase inducer in MS lesions included CD4+ and CD8+ T lymphocytes, B lymphocytes and monocyte/macrophages. The extra-endothelial expression of extracellular matrix metalloproteinase inducer was a marker of the activity of lesions in MS, being present on leucocyte-containing perivascular cuffs but not in inactive lesions. By using a function-blocking antibody, we implicate extracellular matrix metalloproteinase inducer in the adhesion of leucocytes to endothelial cells and determined that its activity was more crucial on leucocytes than on endothelium in leucocyte-endothelial cell engagement in vitro. Extracellular matrix metalloproteinase inducer activity regulated the level of alpha 4 integrin (the target for tysabri) on leucocytes through a mechanism associated with nuclear factor κB signalling. Blocking extracellular matrix metalloproteinase inducer attenuated the transmigration of monocytes and B lymphocytes across a model of the blood-brain barrier in culture.

Conclusion: In summary, we describe the prominence of extracellular matrix metalloproteinase inducer in central nervous system inflammatory perivascular cuffs, emphasize its dual role in matrix metalloproteinase induction and leucocyte adhesion, and highlight the elevation of extracellular matrix metalloproteinase inducer as an orchestrator of the infiltration of leucocytes into the central nervous system parenchyma.

This is further fine detail of the mechanism by which cells get out of the blood and into the brain. It could be a target for a new therapy but as it acts like natalizumab it will be difficult to push this off its perch unless blockade has a better safety profile.

Axonal injury is considered the major cause of chronic disability in multiple sclerosis (MS) patients, however the mechanisms behind remain still unclear. Recently, it was demonstrated that autoantibodies against Neurofascin, a cell adhesion molecule within the adult nervous system, can contribute to the development of axonal pathology in some patients. We compared the ability of the two different isoforms of Neurofascin, Nfasc155 and Nfasc186, to induce a pathogenic antibody response in the Dark Agouti (DA) rat. Animals were immunized with recombinant proteins prior to induction of experimental autoimmune encephalomyelitis (EAE) by adoptive transfer of activated MOG-specific T cells. Only Nfasc186 induced an axopathic autoantibody response in vivo, despite extensive cross reactivity between the two isoforms as shown by ELISA and flow cytometry.

There has been much focus of myelin antigens such as myelin oligodendrocyte glycoprotien as a site for damaging antibodies. However when the blood of MSers is looked at you never find every one with antibodies to any one protein. However this true of virtually all target proteins. However that is not to say that they are not important. In this study they look at Neurofascin. These molecules are important in the axon and myelin interface around the Nodes of Ranvier (the gap between myelin that helps nerve impuslses travel quicker). There are two variants (see picture) and antibodies against the bigger of the two 186Kda verses 155Kda (a da = dalton which is an indicate of the size of the molecule) cause nerve damage in they get into the brain. This is another way that problems are caused in MSers.

Background: To expand current knowledge, this study examined the safety and tolerability of subcutaneous interferon β-1a in MSers with pediatric-onset MS.

Methods: Records from 307 MSers who had received at least 1 injection of subcutaneous interferon β-1a for demyelinating events when aged younger than 18 years were reviewed.

Results: Overall, 168 (54.7%) MSers had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon β-1a or specific to pediatric MSers, 184 (59.9%) had non-serious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment.

Conclusions: Adult doses of subcutaneous interferon β-1a (44 and 22 μg, 3 times weekly) were well tolerated in pediatric MSers and were associated with reduced relapse rates.

"No surprises here; the profile of interferon-beta in childhood-onset MS appears similar to that in adults. I wonder what the new generation drugs will be like, in particular the more efficacious ones. Will they prevent the cognitive impairment or poor cognitive development that is so characteristic of childhood MS?"

"In keeping with my current policy of uploading all of my presentations; the following are my slides that I used in my debate with Dr Brenner at the ABN is Glasgow. I managed to scrape home with a few swing voters; probably my staff who felt sorry for me.""I built up my arguments against the motion by using a fictitious, but quite real, case study. In essence this lady had active MS in that her MRI was very active with an increase in lesion load, gadolinium enhancing lesions and progressive brain atrophy. But as she did not have overt clinical relapses I was not able to escalate her treatment to either fingolimod of natalizumab under the current NICE guidance. I also used surveys I had done to show that the majority of my colleagues in the UK don't use MRI to monitor MS disease activity and neither do they use guidelines that incorporate MRI into decision-making algorithms regarding switching or escalating DMTs. Therefore on the balance of probabilities the Judge did not find me negligent. The debate did however focus attention on NICE guidelines; the current guidelines leave many MSers in no man's land or in the middle of the so called DMT doughnut - with active disease on a platform therapy but not be able to access more effective second-line or escalation therapies as they don't fulfill NICE guidelines.""The solution is obvious we need to lobby the NHS, preferably via the ABN, to change the DMT prescribing guidelines to allow MSers access to more effective therapies early on, i.e. before MS does too much damage. Early aggressive treatment is not for everyone; however, in my opinion MSers should at least have the option of choosing these treatments up front.""I also threw in a curved ball by getting Dr B in the case to prescribe more active DMTs using a private prescription under the NHS; please note this was a fictitious scenario, but quite possible in the 'new NHS'. The socialists in the audience were horrified at Dr B's disregard for the sanctity of the NHS; i.e. free at point of access and equitable.""There are no winners and losers in these debates; the topic was chosen to highlight the thin line we have to tread in trying to keep the NHS affordable for all and our commitments and responsibilities to the individuals who we look after. In my opinion there is no compromise; we need to look after the individual and the politicians and public health doctors can look after the drug budgets and the population. May be this is wrong?"

Dr Brenner 0 - Professor Giovannoni 1(Prof G may have cheated by presenting a fictitious case scenario; unfortunately the rules of engagement had not been defined so this is a moot point)

Saturday, 25 May 2013

The evidence that hypoxia is a precipitating factor in causing early MS lesions includes increased protein levels of hypoxia-inducible factor-1α; presence of the D-110 hypoxia-inducible protein; increased expression of hypoxia-inducible genes in lesions as well as in adjacent normal-appearing white matter (NAWM); loss of myelin-associated glycoprotein in myelin of early MS lesions; a 50% reduction of blood flow through NAWM with areas of lowest blood flow having the greatest probability of lesion development. Why MS-like lesions develop following hypoxemic insults in some individuals but not in others is likely dependent upon the presence of immune predisposing factors that are governed genetically. Hypoperfusion may be due to decreased arterial supply, restricted venous return, or a combination of these. There are clinical trials ongoing or planned to treat chronic cerebrospinal venous insufficiency (CCSVI) through angioplasty. I suggest that it is important that clinical trials addressing vascular issues in MS should examine how the vascular intervention affects white matter perfusion and determine whether the extent of perfusion recovery and maintenance of this recovery is related to functional recovery and maintenance of functional recovery. Consideration should also be given to the possibility of arterial problems playing a role in hypoperfusion in some MS patients.

Some multiple sclerosis (MS) patients reported an improvement after percutaneous transluminal angioplasty (PTA) for chronic cerebrospinal venous insufficiency (CCSVI), despite the lack of correspondence with objective outcome scores. The objective was to assess neurologic and quality of life scores before and after PTA for CCSVI in an observational study after a self-decided approach. 44 consecutive MS patients (21/23 M/F; median age 43 years, SD 9.8) who underwent PTA were evaluated before endovascular treatment for CCSVI and after 12 months. Neurologic outcome was assessed with EDSS, the annualized relapse rate (ARR) and frequency of new lesions at MRI after PTA. Quality of life was evaluated through the MSQoL-54 questionnaire. No modification in the ARR (p = 0.829)

Worsening of disability status (p = 0.002) New lesions at MRI in 29.6 % of patients were found, in contrast to an improvement both in physical and mental domains of MSQoL-54 (p = 0.003). Multiple logistic regression showed EDSS score before PTA to be predictor of an increase of >10 points in MSQoL-54 mental domain (OR 0.52, 95 % CI, 0.31-0.89, p = 0.018). Spontaneously performed approach to CCSVI does not improve clinical and MRI parameters, despite frequent subjective perception of quality of life improvement.Yet another negative study. CCSVI does not improve clinical and MRI parameters, despite frequent subjective perception of quality of life improvement.

Objective: To assess the efficacy and safety of glatiramer acetate (GA) 40 mg administered three times weekly (tiw) compared with placebo in RRMSers.

Methods: This randomized, double-blind study was conducted in 142 sites in 17 countries. RRMSers with at least one documented relapse in the 12 months before screening, or at least two documented relapses in the 24 months before screening, and an Expanded Disability Status Scale score ≤5.5, were randomized 2:1 to receive either subcutaneous (sc) GA 40 mg tiw (1 mL) or placebo for 12 months.

Results: Of 1524 MSers screened, 1404 were randomized to receive GA 40 mg sc tiw (n=943) or placebo (n=461). Ninety-three percent and 91% of MSers in the placebo and GA groups, respectively, completed the 12-month study. GA 40 mg tiw was associated with a 34.0% reduction in risk of confirmed relapses compared with placebo (mean annualized relapse rate 0.331 vs 0.505; p< 0.0001). MSers who received GA 40 mg tiw experienced highly significant reduction (p< 0.0001) in the cumulative number of gadolinium (Gd)-enhancing T1 (44.8%) and new or newly enlarging T2 lesions (34.7%), at months 6 and 12. GA 40 mg tiw was safe and well tolerated. The most common adverse events in the GA group were injection-site reactions (35.5% with GA vs 5.0% with placebo).

Interpretation: GA 40 mg sc tiw is a safe and effective regimen for the treatment of RRMS, providing the convenience of fewer sc injections per week.

"Two days ago it was a new interferon preparation that could be given every 2 weeks or possibly every 4 weeks and now its double-dose glatiramer acetate (Copaxone) that can be give 3X times a week instead of every day. Is this innovation or life-cycle management of blockbuster drugs that are beginning to get ready for the invasion of cheaper biosimilars?"

OBJECTIVE: A double-blind, randomized, controlled study to determine if combined use of interferon beta-1a (IFN) 30ug IM weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in ...

BACKGROUND: Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in MS, these investigators ...

In demyelinating diseases, such as multiple sclerosis, remyelination offers the potential to recover function of viable denuded axons by restoring saltatory conduction and/or protecting from further damage. Mice with genetic reduction of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) exhibit dramatically improved remyelination following experimental demyelination with cuprizone. The current studies are the first to test neurobehavioral outcomes with these gene deletions that improved remyelination. The cuprizone protocols used did not produce overt abnormalities but did reduce bilateral sensorimotor coordination (complex wheel task) and increase sociability (two chamber apparatus with novel mouse). A significant effect of genotype was observed on the complex wheel task but not in the sociability apparatus. Specifically, complex wheel velocities for Fgf2 nulls improved significantly after removal of cuprizone from the diet. This improvement in Fgf2 null mice occurred following either acute (6 wk) or chronic (12 wk) demyelination. Plp/CreERT:Fgfr1fl/fl mice administered tamoxifen at 10 wks of cuprizone treatment to induce Fgfr1 knockdown also showed improved recovery of running velocities on the complex wheels. Therefore, constitutive deletion of Fgf2 or Fgfr1 knockdown in oligodendrocyte lineage cells is sufficient to overcome impairment of sensorimotor coordination after cuprizone demyelination.

An FGF molecule

Fibroblast (connective tissue cell) growth factors make fibroblasts and other cells growth. This study indicates that inhibitors of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) could improve remyelination and this could be associated with functional changes. So yet more cues for remyelination. We need to know how many are the critical key regulators as it is clear to me there are now alot of factors that promote this activity. There is only one way to find out....lets to the the trials.

PML Risk Infographic

Holistic Management of MS ver. 7.0

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